Hypoglycemia, in lay terms known as “low blood sugar” or “insulin shock”, is an undesirable and potentially lethal side-effect of insulin treatment in diabetes mellitus. Hypoglycemia triggers a hypothalamic stress response, resulting in increased activity in the sympathetic nervous system and release of the catecholamine hormones epinephrine and norepinephrine from the adrenal medulla. Catecholamine release into the blood stream induces excitatory or adrenergic responses such as shakiness, increased heart rate and perspiration, and cutaneous vasoconstriction, potentially resulting in paleness and a drop in skin temperature. Over a period of hours, declining blood glucose concentration may ultimately affect the brain and lead to neuroglycopenic symptoms such as dizziness, impaired coordination, mental confusion, and altered behaviour. If left untreated, extreme hypoglycemia may result in coma, brain damage or death.
Upon becoming aware of early autonomic indicators like increased perspiration or heart palpitations, a diabetic individual can easily correct mild hypoglycemia by taking fast-acting carbohydrate, such as glucose tablets, fruit juice, or candies. However, cognizance of adrenergic symptoms may be compromised by diabetic autonomic neuropathy, a nervous disorder that is likely attributable to a combination of factors including high blood glucose and a long duration of diabetes.
Cognizance of physical symptoms is also reduced or inhibited by “hypoglycemia unawareness”, an increased tolerance to low blood sugar which develops as a result of repeated hypoglycemic episodes. Since epinephrine response is blunted during sleep and as a consequence of hypoglycemia unawareness caused by neuropathy or frequent lows, a sleeping diabetic individual may not awaken until after nueroglycopenic symptoms are established, in which case the individual in a confused mental state may neglect or even resist treatment. Therefore, it is particularly important to provide methods of preventing nocturnal hypoglycemic events at the earliest possible stage of detection, so that development of hypoglycemia unawareness is avoided.
One approach which may be applied to detection of nocturnal hypoglycemia is described by Potts and Tierney in U.S. Patent Application Publication 2002/0106709. Potts and Tierney disclose methods and devices for prediction of hypoglycemic events based on analysis of discrete sampled values of glucose, body temperature, and skin conductance. Skin conductance is directly representative of the adrenergic symptom of perspiration. In the preferred embodiment, glucose is measured by a GlucoWatch G2 Biographer (Cyngnus Inc. Redwood City Calif.), rather than by blood sampling.
The GlucoWatch is applied at the wrist and withdraws glucose in the subcutaneous interstitial fluid into a hydrogel pad by means of reverse-iontophoresis, a process in which an osmotic flow through the epidermis is driven by a current applied at the skin surface. Hypoglycemic detection thresholds for interstitial glucose, skin temperature, and skin conductance measurements are derived for a given individual from historical data collected over extended time periods (days, weeks or months). Methods are proposed by Potts and Tierney for predicting a future glucose value at time (n+1) from extrapolation of past glucose values up to and including time (n). A hypoglycemic event is predicted when comparison of the extrapolated interstitial glucose to the glucose threshold indicates a hypoglycemic event, provided that comparison of either skin temperature or conductance, or both, to their respective thresholds also indicates a hypoglycemic event.
In principle, therefore, methods disclosed by Potts and Tierney rely on the presence of adrenergic symptoms to validate an interstitial glucose reading suggestive of a low blood glucose concentration. However, as the glucose reading derived by the GlucoWatch is not obtained from the blood, the manufacturer of the instrument directs users to confirm readings by glucometer under certain circumstances, such as during a hypoglycemic episode.
A central limitation of methods described by Potts and Tierney is the uncertainty of the subcutaneous glucose reading as electro-osmotically obtained from the interstitial fluid. Clinical performance of the GlucoWatch Biographer has been reviewed by the US Food and Drug Administration as documented in “Summary of Safety and Effectiveness Data” (SSED), PMA no. P990026 (Mar. 22, 2001), and as documented in the SSED for PMA supplement P990026/1008 (Aug. 26, 2002). As reported in these FDA SSED publications, individual GlucoWatch readings can differ substantially from concurrently recorded blood glucose values, such individual differences being somewhat unpredictable and necessitating interpretation based on trends and patterns seen with several sequential readings over time.
The GlucoWatch requires 20 minutes to produce each glucose reading, and as such, dynamic response of the interstitial glucose measurement may substantially lag blood glucose variations. Prediction of the glucose value as disclosed by Potts and Tierney is therefore an attempt to overcome the slow response of the GlucoWatch to changes in interstitial glucose concentration. However, extrapolation of an upcoming value 20 minutes in advance based on uncertain prior values may invalidate the hypoglycemic threshold comparison, and so methods as disclosed by Potts and Tierney require additional temperature and skin conductivity analyses to either support or reject the comparison result.
As a means of reducing noise in the glucose values and thereby obtaining improved prediction, Potts and Tierney disclose a linear prediction equation based on moving average exponential smoothing over a 60-minute interval, however, the equation utilizes only the current glucose reading and previous two readings to extrapolate the prediction result. Therefore, the protracted sample processing time of the GlucoWatch also limits the amount of data that may be meaningfully applied to obtain useful predictions of the interstitial glucose.
Further practical limitations of the GlucoWatch include a three-hour warm-up interval following application to the wrist, which must be completed prior to initiation of monitoring. Once monitoring has been initiated, rapid temperature change or excessive perspiration can cause the GlucoWatch to discard glucose measurements, and if such conditions persist, the GlucoWatch will cease monitoring altogether.
Skin irritation and/or itching from iontophoresis is experienced by most users, and as such the GlucoWatch must be relocated to a new site on the arm, or to the alternate arm, prior to each use. Occasional blisters may be observed, and people with sensitive skin may experience more intense, although temporary, redness and itching. In consideration of skin irritations induced, the GlucoWatch must not be applied at sites having eczema, cuts, sunburn, razor burn or scarring, and to be effective the GlucoWatch cannot be applied over hair.
Given that induced skin irritation may be tolerable for some users, and that inconvenience of a protracted warm-up delay prior to use may be acceptable, and that removal of hair from the upper limbs is not objectionable, the 12-hour replacement cycle of the disposable hydrogel pad creates a significant economic burden for those desiring or requiring frequent glucose readings on a ongoing basis (Trecroci, D., Diabetes Interview, 11:28–30 (2002)). Due to performance limitations, side-effects, and unmanageable operating costs, the GlucoWatch may not become widely utilized, particularly for those individuals requiring nocturnal monitoring for hypoglycemic episodes over a lifetime.
Alternate approaches to the problem of detecting nocturnal hypoglycemia predate development of the GlucoWatch Biographer. Such methods rely solely on automated monitoring for early-stage adrenergic symptoms, such as perspiration and skin temperature drop, as opposed to direct measurement of blood, skin or interstitial glucose concentration. Detection of pertinent symptoms causes an audible alarm to be produced, awakening the user who must then confirm the condition by blood sample, this also being the case for the GlucoWatch as described above. An advantage of a symptom-based approach is that it may be implemented as a small, relatively inexpensive electronic monitor that may be conveniently worn, like the GlucoWatch, at the wrist or other sites. Additional advantages include low operating cost, because the alternate approaches do not employ a disposable component, and no skin irritation, because the alternates to the GlucoWatch do not employ reverse-iontophoresis when determining either skin temperature or perspiration.
However, acceptance of simple electronic monitors has been limited by their inability to reliably distinguish symptoms of hypoglycemia from ongoing physiological variations not associated with hypoglycemia, or from transient environmental disturbances. Annoying false alarms may thus be produced as a result of, for example, increased perspiration or reduced skin blood flow arising from the normal autonomic function of the hypothalamus in maintaining core body temperature. Similarly, false alarms may also result in response to the physiological effects of medication or infection insofar as these influence the thermoregulatory mechanism, or other responses of the autonomic nervous system. Transient disturbances not associated with any autonomic process, for example air drafts and body movement, may also result in false alarms if means are not provided to mitigate such noise sources.
Monitors that combine measurement of a temperature with measurement of skin moisture or perspiration are disclosed by Ouellete in U.S. Pat. No. 5,938,593, and by Fienberg et al. in U.S. Pat. No. 5,897,505. Additionally, apparatus which measure skin temperature and produce an alarm signal when the temperature either rises above or falls below a threshold are also disclosed by Hong in U.S. Pat. No. 5,559,497, and by Cocatre-Zilgien in U.S. Pat. No. 5,844,862. Monitors intended for detecting hypoglycemic symptoms in a diabetic individual, combining measurement of perspiration, temperature or both with means for producing an alarm are also disclosed in U.S. Pat. No. 4,178,916 to McNamara, U.S. Pat. No. 4,365,637 to Johnson, and U.S. Pat. No. 4,509,531 to Ward.
U.S. Pat. No. 4,178,916 to McNamara describes a diabetic insulin alarm system that is applied to the wrist and which produces an alarm if the temperature measured at the skin surface drops below a threshold. McNamara also describes means which produce an alarm if perspiration at the wrist increases such that the galvanic skin resistance between two electrodes correspondingly decreases below a threshold. The alarm threshold for temperature is manually set by the wearer of the invention, via a potentiometer control in the electrical circuitry of the invention. However, the alarm threshold for the galvanic skin resistance cannot be varied in the invention as described by McNamara.
U.S. Pat. No. 4,365,637 to Johnson discloses a self-contained wearable device which is applied to the wrist and which senses perspiration only. The device produces an audible indication when build up of perspiration on the skin causes the galvanic skin resistance between two electrodes to drop below a threshold. As disclosed, the threshold may be manually set by either of two means: by a potentiometer control in the electrical circuitry of the invention, or by screw adjustments which can variably displace the skin resistance electrodes away from the skin surface, thereby mechanically achieving a form of sensitivity control.
A limitation of devices described by McNamara and Johnson is they do not include automated means to compensate the apparatus for skin temperature or resistance variations arising from physiological responses not associated with hypoglycemia. If the manual threshold adjustments provided are not correctly set by the user, or if changes to the threshold adjustments are not made during the monitoring period to compensate for ongoing and non-symptomatic physiological variation, these devices may not detect an approaching hypoglycemic episode or, conversely, may produce a large number of annoying false alarms. Given the application of nocturnal monitoring, corrective threshold adjustments by the user are furthermore impractical.
The device disclosed by McNarama in U.S. Pat. No. 4,178,916 includes telemetry means for broadcasting the alarm signal to a nearby radio receiver. The Sleep Sentry™, a device manufactured by Teledyne Avionics of Charlottesville Va. and similar to the McNamara '916 device (but without telemetry means) has been clinically evaluated. In a home-based study of 24 pediatric patients conducted over 1444 patient-nights, Hansen et al. found that the Sleep Sentry™ produced a total of 192 alarms, 150 of the alarms being false and only 42 of which were deemed valid by means of Chemstrip bG value under 100 mg/dl in combination with hypoglycemic symptoms alleviated by subsequent feeding (Diabetes Care, 6:597–600 (1983)). A total of 46 hypoglycemic episodes were detected by the latter empirical triad, indicating that the Sleep Sentry™ produced at least four false negatives during the study.
In a subsequent clinical evaluation by Clarke et al. (Diabetes Care, 11:630–35 (1988)), only 10 of 18 adult diabetic subjects experienced an alarm from the Sleep Sentry™ during a 2-hour controlled infusion of insulin at 40 mU/(kg-hr), despite a mean plasma glucose nadir in the 50–53 mg/dl range as obtained by concurrent venous blood sampling. These results demonstrate how preset, non-adaptive thresholds for skin temperature and resistance in a monitoring device, such as described by McNamara or Johnson, may result in either false positive or false negative error rates that are unacceptably high, and consequently, such devices are not widely utilized.
A further limitation of inventions as disclosed by McNamara and Johnson is that DC current is applied to a pair of electrodes to determine the galvanic skin resistance. Even though the current may be only a few microamps, sensitive individuals may experience skin irritation after long exposure by means of iontophoresis. With the Teledyne Sleep Sentry™, iontophoretic irritation at the electrodes was observed by Hansen et al. in 6 of the 24 subjects participating in the study.
U.S. Pat. No. 4,509,531 to Ward discloses a personal physiological monitor similar to the invention of McNamara, buy the Ward device includes a temperature reference that is automatically established and which is updated periodically to accommodate slowly changing non-symptomatic skin temperature variations. Therefore, the temperature alarm threshold of the Ward invention is not manually preset to a single value but varies in response to discrete samples of the skin temperature itself. Further improvements include the use of pulsed current and enlarged electrodes to measure the galvanic skin resistance, thereby preventing skin irritation from iontophoresis due to the very low current density that is achieved.
A limitation of the invention disclosed by Ward is that the alarm threshold for perspiration represented by the galvanic skin resistance cannot be varied, this being the same limitation as described previously for the McNamara invention. As such, inventions disclosed by Ward and McNamara are incapable of compensating for non-symptomatic variations in perspiration, such as increasing perspiration which may be a hypothalamic thermoregulatory response to increasing core temperature. Although Johnson discloses manual means for adjusting the perspiration alarm threshold, the invention of Johnson is limited in that it does not automatically compensate for perspiration not associated with hypoglycemia.
Although improved when compared to the devices disclosed by McNamara and Johnson, the personal physiological monitor described by Ward has a number of additional limitations. Alarm indicia related to temperature are generated by the Ward invention only if the skin temperature drops a predetermined amount below the reference temperature. Since the predetermined amount cannot be varied, a hypoglycemic temperature drop smaller than the predetermined amount may go undetected. Conversely, if the predetermined amount is too small, false alarms may result from non-physiological temperature drops caused by air drafts or unconscious movement of the wrist to which the invention is applied.
The temperature reference is updated at arbitrary elapsed times as measured from device activation, rather than as required to compensate for any basal physiological process. As a result, the temperature reference may be inappropriately modified at a time when the skin temperature has dropped to a level incrementally above, but still not less than, the temperature alarm threshold derived from the reference, potentially resulting in an undetected hypoglycemic event.
Another limitation is that the first temperature reference is obtained immediately upon activating the monitor. Therefore, if the monitor is activated before sufficient time has elapsed to allow the device temperature to equilibrate with the skin temperature, an initial temperature reference which is falsely low may be obtained, resulting in reduced ability to detect a drop in skin temperature from the normative basal level. The temperature reference is acquired from a single sample of the skin temperature, and thus the temperature reference may be falsely high or low if the monitor was disturbed at the sample instant, for example, by body movement or environmental disturbance such as an air draft. Similarly, alarms are declared if a single instance of the skin temperature or resistance falls below the corresponding threshold, and so symptom detection can also be easily corrupted by transient disturbances such as air drafts or unconscious movement.
A final and practical limitation of the invention disclosed by Ward is that no means are provided to alert the user that internal batteries which power the monitor are approaching, but have not reached, full discharge. Therefore, it may be possible for a user to initially activate the device, but then experience unreliable operation after a few hours of continuous monitoring.
To overcome limitations of the prior art, one object of the present invention is to provide improved apparatus for detecting symptoms of hypoglycemia.